The prevalence of insulin resistance in glucose intolerant subjects has long been recognized. Reaven et al (American Journal of Medicine 1976, 60, 80) used a continuous infusion of glucose and insulin (insulin/glucose clamp technique) and oral glucose tolerance tests to demonstrate that insulin resistance existed in a diverse group of nonobese, nonketotic subjects. These subjects ranged from borderline glucose tolerant to overt, fasting hyperglyceriaa. The diabetic groups in these studies included both insulin dependent (EDDM) and noninsulin dependent (NIEDDM) subjects.
Coincident with sustained insulin resistance is the more easily determined hyperinsulinemia, which can be measured by accurate determination of circulating plasma insulin concentration in the plasma of subjects. Hyperinsulinemia can be present as a result of insulin resistance, such as is in obese and/or diabetic (NIDDM) subjects and/or glucose intolerant subjects, or in IDDM subjects, as a consequence of over injection of insulin compared with normal physiological release of the hormone by the endocrine pancreas.
The association of hyperinsulinemia with obesity and with ischernic diseases of the large blood vessels (e.g. atherosclerosis) has been well established by numerous experimental, clinical and epidemiological studies (summarized by Stout, Metabolism 1985, 34, 7, and in more detail by Pyorala et al, Diabetes/Metabolism Reviews 1987, 3, 463). Statistically significant plasma insulin elevations at 1 and 2 hours after oral glucose load correlates with an increased risk of coronary heart disease.
Since most of these studies actually excluded diabetic subjects, data relating the risk of atherosclerotic diseases to the diabetic condition are not as numerous, but point in the same direction as for nondiabetic subjects (Pyorala et al). However, the incidence of atherosclerotic diseases in morbidity and mortality statistics in the diabetic population exceeds that of the nondiabetic population (Pyorala et al; Jarrett Diabetes/Metabolism Reviews 1989,5, 547; Harris et al, Mortality from diabetes, in Diabetes in America 1985).
The independent risk factors obesity and hypertension for atherosclerotic diseases are also associated with insulin resistance. Using a combination of insulin/glucose clamps, tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (principally muscle) and correlates directly with the severity of hypertension (DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173). In hypertension of the obese, insulin resistance generates hyperinsulinemia, which is recruited as a mechanism to limit further weight gain via thermogenesis, but insulin also increases renal sodium reabsorption and stimulates the sympathetic nervous system in kidneys, heart, and vasculature, creating hypertension.
It is now appreciated that insulin resistance is usually the result of a defect in the insulin receptor signaling system, at a site post binding of insulin to the receptor. Accumulated scientific evidence demonstrating insulin resistance in the major tissues which respond to insulin (muscle, liver, adipose), strongly suggests that a defect in insulin signal transduction resides at an early step in this cascade, specifically at the insulin receptor kinase activity, which appears to be diminished (reviewed by Haring, Diabetalogia 1991, 34, 848).
Protein-tyrosine phosphatases (PTPases) play an important role in the regulation of phosphorylation of proteins. The interaction of insulin with its receptor leads to phosphorylation of certain tyrosine molecules within the receptor protein, thus activating the receptor kinase. PTPases dephosphorylate the activated insulin receptor, attenuating the tyrosine kinase activity. PTPases can also modulate post-receptor signaling by catalyzing the dephosphorylation of cellular substrates of the insulin receptor kinase. The enzymes that appear most likely to closely associate with the insulin receptor and therefore, most likely to regulate the insulin receptor kinase activity, include PTP1B, LAR, PTPxcex1 and SH-PTP2 (B. J. Goldstein, J. Cellular Biochemistry 1992, 48, 33; B. J. Goldstein, Receptor 1993, 3, 1-15,; F. Ahmad and B. J. Goldstein Biochim. Biophys Acta 1995, 1248, 57-69).
McGuire et al. (Diabetes 1991, 40, 939), demonstrated that nondiabetic glucose intolerant subjects possessed significantly elevated levels of PTPase activity in muscle tissue vs. normal subjects, and that insulin infusion failed to suppress PTPase activity as it did in insulin sensitive subjects.
Meyerovitch et al (J. Clinical Invest. 1989, 84, 976) observed significantly increased PTPase activity in the livers of two rodent models of IDDM, the genetically diabetic BB rat, and the STZ-induced diabetic rat. Sredy et al (Metabolism, 44, 1074, 1995) observed similar increased PTPase activity in the livers of obese, diabetic ob/ob mice, a genetic rodent model of NIDDM.
The compounds of this invention have been shown to inhibit PTPases derived from rat liver microsomes and human-derived recombinant PTPase-1B (hPTP-1B) in vitro. They are useful in the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels.
C. Goldenberg et al., Eur. J. Med. Chem.xe2x80x94Chim. Ther. 1977, 12(1), 81-86 and M. Descamps et al., (DE 2710047) disclosed compounds of formula A. 
G. J. Cuilinan and K. J. Fahey (U.S. Pat. No. 5,596,106 A and WO 960201) disclose arylbenzo[b]thiophene and benzo[b]furan compounds B and C as cannabinoid receptor antagonists. 
H. Grote (DE 3342624 A1) disclose Benzarone derivatives D for treating venous and arterial ailments. 
(R, R1, R2 and R3 is H, alkoxy, acyloxy, OH, SO3H; R4 is H, acyl, HSO2)
T. Eckert (DE 3110460 and Arch. Pharm. (Weinheim, Ger.) 1982, 315(6), 569-570 discloses sodium benzaron sulfate E. 
None of the above disclosures (A-E) contained the appropriate substitution necessary for in vitro PTPase inhibition activity.
This invention provides a compound of formula I having the structure 
wherein
R1 and R2 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, halogen, perfluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, phenyl or phenyl substituted with trifluoromethyl, chloro, methoxy, or trifluoromethoxy;
R3 and R4 are each, independently, hydrogen, carboxy, hydroxy, hydoxyalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms, perfluoroalkanoyloxy of 2-7 carbon atoms, arylalkoxy of 7-15 carbon atoms, aryloxy of 6-12 carbon atoms, aroyloxy of 7-13 carbon atoms, aryloxycarbonyl of 7-13 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, tetrazolyl, mercapto, nitrile, nitro, amino, xe2x80x94NHSO2CF3, carbamoyl, formyl, halogen, acylamino, 3-hydroxy-cyclobut-3-ene-4-yl-1,2-dione, or tetronic acid;
R5 is hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, naphthalenylmethyl, benzyl or benzyl substituted with halogen,
R6 and R7 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or perfluoroaLkyl of 1-6 carbon atoms, or R6 and R7 may be taken together as a diene unit having the structure xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
W is S or O,
X is xe2x80x94NR8CH2xe2x80x94, xe2x80x94NR8xe2x80x94, or O;
R8 is hydrogen or alkyl of 1-6 carbon atoms;
Y is carbonyl, methylene, xe2x80x94CH2CH2xe2x80x94, or xe2x80x94NHCH2xe2x80x94;
Z is phenyl, pyridyl, naphthyl, thienyl, furyl, pyrrolyl, pyrazolyl, isoxazolyl, or isothiazolyl;
or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, when a compound of this invention contains a carboxylate or phenolic moiety, or similar moiety capable of forming base addition salts.
Alkyl includes both straight chain as well as branched moieties. Halogen means bromine, chlorine, fluorine, and iodine. It is preferred that the aryl portion of the aryl, arylkyl, arylalkoxy, aryloxy, aroyloxy, or aryloxycarbonyl substituent is a phenyl, naphthyl or 1,4-benzodioxan-5-yl group, with phenyl being most preferred. The aryl moiety may be optionally mono-, di-, or tri-substituted with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each of the alkyl groups is of 1-6 carbon atoms, nitro, cyano, xe2x80x94CO2H, alkanoyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 carbon atoms.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
Preferred compounds of this invention are those compounds of Formula I,
wherein
R1 and R2 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, halogen, perfluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, phenyl or phenyl substituted with trifluoromethyl, chioro, methoxy, or trifluoromethoxy;
R3 and R4 are each, independently, hydrogen, carboxy, hydroxy, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms, perfluoroalkanoyloxy of 2-7 carbon atoms, aroyloxy of 7-13 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, aryloxycarbonyl of 7-13 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, tetrazolyl, mercapto, nitrile, amino, xe2x80x94NHSO2CF3, carbamoyl, formyl, acylamino of 2-7 carbon atoms;
R5 is hydrogen, alkyl of 1-6 carbon atoms, naphthalenylmethyl, benzyl or benzyl substituted with halogen;
R6 and R7 are each, independently hydrogen or alkyl of 1-6 carbon atoms or R6 and R7 may be taken together as a diene unit having the structure xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
W is S or O,
X is xe2x80x94NHCH2xe2x80x94, or O;
Y is carbonyl, methylene, xe2x80x94CH2CH2xe2x80x94, or xe2x80x94NHCH2xe2x80x94;
Z is phenyl, pyridyl, naphthyl, thienyl, furyl, pyrrolyl, pyrazolyl, isoxazolyl, or isothiazolyl;
or a pharmaceutically acceptable salt thereof.
More preferred compounds of this invention are those compounds of Formula I,
wherein
R1 and R2 are each, independently, hydrogen, iodo, phenyl, thienyl, alkyl of 1-6 carbon atoms, bromo, or cycloalkyl of 3-8 carbon atoms,
R3 and R4 are each, independently, hydrogen, carboxy, hydroxy, methyl, or acetoxy;
R5 is hydrogen, alkyl of 1-6 carbon atoms, naphthalenylmethyl, benzyl or benzyl substituted with bromine;
R6 and R7 are each, independently, hydrogen or methyl, or R6 and R7 may be taken together as a diene unit having the structure xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
Wis S or O,
X is xe2x80x94NHCH2xe2x80x94, or O;
Y is carbonyl, methylene, xe2x80x94CH2CH2xe2x80x94, xe2x80x94NHCH2xe2x80x94;
Z is phenyl, or pyrazolyl;
or a pharmaceutically acceptable salt thereof.
Specifically preferred compounds of the present invention are set forth below:
4-[2,6-Dibromo-4-(2-ethyl-benzofuran-3-carbonyl)-phenoxysulfonyl]-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-[5xe2x80x2-(2-Butyl-benzofuran-3-carbonyl)-[1,1xe2x80x2; 3xe2x80x21xe2x80x3]terphenyl-2xe2x80x2-yloxysulfonyl]-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-[4-(2-Ethyl-benzofuran-3-carbonyl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-[4-(2-Ethyl-benzofuran-3-carbonyl)-2,6-diisopropyl-phenoxysulfonyll-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-[4-(2-Benzyl4,5-dimethyl-furan-3-carbonyl)-2,6-diisopropyl-phenoxysulfonyl]-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-[5xe2x80x2-(2-Ethyl-benzofuran-3-carbonyl)-[1,1xe2x80x2; 3xe2x80x2,1xe2x80x3]terphenyl-2xe2x80x2-yloxysulfonyl]-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-[5-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-3-methyl-biphenyl-2-yloxysulfonyl]-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-[4-(4,5-Dimethyl-2-naphthalen-2-ylmethyl-ftiran-3-carbonyl)-2,6-diisopropyl-phenoxysulfonyl]-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-{4-[2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2,6-diisopropyl-phenoxysulfonyl}-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-{4-[2-(3-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2,6-diisopropyl-phenoxysulfonyl}-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-{4-[2-(4-Bromo-benzyl)4,5-dimethyl-furan-3-carbonyl]-2,6-diisopropyl-phenoxysulfonyl}-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
2-Acetoxy-4-{4-[2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-benzoic acid or a pharmaceutically acceptable salt thereof.
2-Acetoxy-4-{4-[2-(4-Bromo-benzyl)-4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-benzoic acid or a pharmaceutically acceptable salt thereof.
2-Acetoxy4-[4-(2-benzyl-4,5-dimethyl-tbiophene-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-benzoic acid or a pharmaceutically acceptable salt thereof.
2-Acetoxy-4-[4-(2-benzyl4,5-dimethyl-furan-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-benzoic acid or a pharmaceutically acceptable salt thereof.
4-[4-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-2,6-diethyl-phenoxysulfonyll-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
1-Methyl-1H-pyrazole-4-sulfonic acid 4-[2-(4-bromo-benzyl)-4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenyl ester or a pharmaceutically acceptable salt thereof.
4-{4-[2-(2-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-{4-[2-(4-Bromo-benzyl)-4,5-dirnethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-[4-(2-Benzyl-4,5-dimethyl-thiophene-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-[4-(2-Benzyl-4,5-dimethyl-furan-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-{4-[2-(4-Bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-[4-(2-Butyl-benzofuran-3-ylmethyl)-phenoxysulfonyl]-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof
4-[4-(2-Butyl-benzofuran-3-carbonyl)-phenoxysulfonyl]-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-{4-[2-(2-Butyl-benzofuran-3-yl)-ethyl]-phenoxysulfonyl}-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
2-Acetoxy4-{4-[2-(2-butyl-benzofuran-3-yl)-ethyl]-phenoxysulfonyl}-benzoic acid or a pharmaceutically acceptable salt thereof.
4-{4-[(2-Butyl-benzofuran-3-ylmethyl)-arnino]-phenoxysulfonyl}-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
4-{4-[2-(2-Benzyl-benzo[b]thiophen-3-yl)thyl]-phenoxysulfonyl}-2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof.
The compounds of this invention were be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using to literature procedures. These schemes show the preparation of representative compounds of this invention. 
In Scheme 1, 2, 3-dimethylthiophene (II: W is S) is prepared from commercially available 3-methyl-thiophene-carboxaldehyde using Wolff-Kishner conditions (hydrazine followed by KOHiethylene glycol reflux). Compound (U) is treated with one to 1.3 molar equivalents of an alkyl lithium reagent such as N-butyl lithium most preferably in a nonprotic solvent such as THF at temperatures ranging from xe2x88x9278xc2x0 C. to room temperature under an inert atmosphere such as nitrogen or argon to provide the 2-lithiated-thiophene or furan derivative. This lithiated analog is reacted in situ with one or more molar equivalents of benzaldehyde, generally at xe2x88x9278xc2x0 C. to room temperature for 5 min to 3 h to provide the compound of formula (III: Q is OH). The hydroxy group of (III: Q is OH) can be removed by a number of reduction procedures such as hydrogenation using palladium catalysts to produce the compound of formula (III: Q is H) but is most conveniently removed using the method of Nutaitis, et. al. (Org. Prep. and Proceed. Int. 1991, 23, 403-411) in which (III: Q is OH; W is S or O) is stirred with one to ten molar equivalents of sodium borohydride in a suitable solvent such as ether, THF or dichioromethane at 0xc2x0 C. to room temperature and one to fifty molar equivalents of trifluoroacetic acid is slowly added over a 15 min to 3 h period to produce the compound of formula (III: Q is H). Alternatively, the 2-lithiated analog of compound (II) in a nonprotic solvent such as THF can be reacted with one or more molar equivalents of a benzyl halide such as benzyl bromide (PhCH2Br) at xe2x88x9278xc2x0 C. to room temperature to directly provide the compound of formula (III: Q is H; W is S or O).
The compounds of formula (III: Q is H) can be acylated with one or more molar equivalents of a commercially available benzoic acid chloride of formula (IV: X is O-alkyl) to produce the acylated derivative of formula (V: X is O-alkyl). This acylation is accomplished most readily using a one to five molar equivalents of a Lewis acid catalyst such as tin tetrachloride or aluminum chloride in an inert solvent such as dichioromethane, 1,2-dichloroethane or carbon disulfide, generally at temperatures such as xe2x88x9278xc2x0 C. to room temperature. The benzoic acid chloride (IV: X is xe2x80x94O-alkyl). is prepared from the corresponding benzoic acid by standard procedures using reagents such as oxalyl chloride and thionyl chloride. The starting benzoic acid of the benzoic acid chloride (IV: X is O-alkyl) is commercially available or can be easily prepared by known procedures For example, the acid starting material for benzoic acid chloride (IV) can be prepared using a modification of the method of Schuster, et al., J. Org. Chem. 1988, 53, 5819. Thus commercially available 2, 6-diisopropyl phenol is brominated in the 4-position (bromine/acetic acid), methylated (iodomethane/potassium carbonate/DMF), reacted with n-butyl lithium to effect lithium halogen exchange and the resultant organolithium species is reacted with carbon dioxide to provide 3, 5-diisopropyl, 4-methoxy benzoic acid. Alternatively, the commercially available 2,6-(mono or disubstituted)phenols can be methylated (iodomethane/potassium carbonate/DMF), acylated in the 4-position with 2-chlorobenzoyl chloride in the presence of aluminum chloride in an inert solvent such as dichloromethane, generally at ambient temperature and reacted with potassium-t-butoxide in H2O/ethylene glycol dimethyl ether at ambient temperature to give the desired 2,6-(mono or disubstituted)benzoic acid.
The conversion of the alkyl ether compound (V: X is O-alkyl) to the phenol compound (Va: X is OH) is generally best accomplished using one to ten molar equivalents of a strong Lewis acid such as a trihaloborane, most conveniently tribromoborane. The reaction is best performed at xe2x88x9278xc2x0 C. with warming to 0xc2x0 C.
The compounds of formula (Va: X is OH) can be sulfonylated on the phenolic oxygen using one or more molar equivalents of suitable sulfonylating agent (VI) to provide the sulfonic acid esters of formula (I: Y is carbonyl). The sulfonylating agent (VI) is generally a aryl or heteroaryl sulfonic acid chloride. The reaction is run under standard conditions using a suitable base such sodium hydride, pyridine or Tris base in an appropriate solvent such as dichloromethane, THF or H2O at temperatures from 0xc2x0 C. to ambient temperature. The starting aryl or heteroaryl sulfonic acid chloride is commercially available or can be easily prepared by known procedures. The aryl or heteroaryl sulfonic acid chloride can be prepared by reacting the aryl or heteroaryl sulfonic acid with one or more molar equivalents of oxalyl chloride or thionyl chloride, in a suitable solvent such as dichloromethane, chloroform or diethyl ether, to afford the aryl or heteroaryl sulfonic acid chloride. This reaction is often catalyzed by adding small amounts (0.01 to 0.1 molar equivalents) of dimethylformamide. Alternatively, the aryl or heteroaryl sulfonic acid chloride can prepared using a modification of Barraclough, et al., Arch. Pharm. (Weinheim) 1990, 323, 507. Thus, the aniline of commercially available 4-aminosalicylic acid sodium salt dihydrate is diazotized with sodium nitrite in HOAc/HCl at xe2x88x9210xc2x0 C. and the subsequent the diazonium salt can converted to the sulfonyl chloride by introduction of sulfur dioxide into the reaction in the presence of copper (I) chloride.
The groups R3 and R4 connected to Z can be further derivatized. For example, when R3 or R4 is an ester of a carboxylic acid or alcohol the compound can be transformed into the respective carboxylic acid or alcohol analog using standard conditions. The conditions to effect these transformations include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0xc2x0 C. to 40xc2x0 C. When R3 or R4 is a carboxylic acid or ester the compound can be reduced to the respective primary alcohol analog using standard conditions such as lithium aluminum hydride in ethyl ether. When R3 or R4 is an aldehyde or ketone the compound can be reduced to the respective primary alcohol analog using a metal catalyst, by sodium in alcohol, sodium borohydride and by lithium aluminum hydride. When R3 or R4 is an ether, the compound can be transformed to the free alcohol by using one to ten molar equivalents of a strong Lewis acid such as a trihaloborane, most conveniently tribromoborane in a halocarbon solvent such as dichloromethane. When R3 or R4 is an alcohol the compound can be oxidized to the respective aldehyde, carboxylic acid or ketone analog using a transition metal oxidant (chromium trioxide-pyridine, pyridinium chlorochromate, manganese dioxide) in an inert solvent such as ether, dichloromethane. Alcohols can also be oxidized using DMSO with a number of electrophilic molecules (dicyclohexylcarbodiimide, acetic anhydride, trifluoro acetic anhydride, oxalyl chloride and sulfur dioxide). When R3 or R4 is a carboxylic acid the compound can be transformed into a carboxylic acid amide analog. This transformation can be accomplished using standard methods to effect carboxylic acid to carboxylic acid amide transformations. These methods include converting the acid to an activated acid and reacting with one or more molar equivalents of the desired amine. Amines in this category include ammonia in the form of ammonium hydroxide, hydroxyl amine and 2-aminopropionitrile. Methods to activate the carboxylic acid include reacting said acid with one or more molar equivalents of oxalyl chloride or thionyl chloride to afford the carboxylic acid chloride in a suitable solvent such as dichloromethane, chloroform or diethyl ether. This reaction is often catalyzed by adding small amounts (0.01 to 0.1 molar equivalents) of dimethylformamide. Other methods to activate the carboxylic acid include reacting said acid with one or more molar equivalents dicyclohexylcarbodiimide with or without one or more molar equivalents of hydroxybenzotriazole in a suitable solvent such as dichloromethane or dimethylformamide at temperatures ranging from 0xc2x0 C. to 60xc2x0 C. When R3 or R4 is nitro, the compound can be reduced to the respective amino compound most readily using tin dichloride in ethylacetate at 40 to 100xc2x0 C. or with hydrazine and Montmorillnite clay in ethanol at 40 to 100xc2x0 C. or by catalytic hydrogenation in the presence of a catalyst such as palladium on carbon. When R3 or R4 is an amino or an alcohol, the compound can be acylated using one or more molar equivalents of suitable acylating agent. The acylating agent is generally a lower alkyl or aryl carboxylic acid anhydride or a lower alkyl or aryl carboxylic acid chloride. The reaction is run under standard conditions, for example the use of pyridine as solvent with or without a co-solvent such as dichloromethane at 0xc2x0 C. to room temperature. When R3 or R4 is an alcohol it can be acylated with a lower alkyl or aryl carboxylic acid anhydride in the presence of magnesium iodide in diethyl ether at ambient temperature to reflux. When R3 or R4 is a nitrile it can be reduced to the aminoalkyl compound by tin (II) chloride in refluxing ethyl acetate or by catalytic hydrogenation in the presence of a catalyst such as Raney nickel or by lithium aluminum hydride in an inert solvent such as ether. When R3 or R4 is a nitrile it can be converted to a carboxylic acid amide using standard conditions such as HCl/H2O at ambient temperatures to reflux or a milder procedure involves the reaction of the nitrile with an alkaline solution of hydrogen peroxide. When R3 or R4 is halogen or trifluoromethanesulfonate it can be converted to a 3-hydroxy-cyclobut-3-ene-4-yl-1,2-dione by methodology of Liebeskind et. al. (J. Org. Chem. 1990, 55, 5359). When R3 or R4 is an alcohol can be alkylated with a suitable alkylating agent such as one or more molar equivalents of alkyl halide in the presence a base such as potassium carbonate or sodium hydroxide in a suitable solvent such as TBF, DMF or DMSO at temperatures ranging from 0xc2x0 C. to 60xc2x0 C. When R3 or R4 is a carboxylic acid, the compound can be coupled to tetronic acid with a coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in the presence of a base such as triethylamine or DMAP in a suitable solvent such as DMF. 
The following method will prepare derivatives of formula (V: Y is methylene) that can utilized in Scheme 1 to prepare compounds of formula (I: Y is methylene). The ketone (V: Y is carbonyl) can be reduced with lithium aluminum hydride in an aprotic solvent such as THF at ambient temperature to give the alcohol (VII). Further reduction of alcohol (VII) with triethylsilane in the presence of boron trifluoride diethyl etherate provides the methylene compound (V: Y is methylene). The compounds prepared in Scheme 2 of formula (V: Y is methylene) can be further modified synthetically in Scheme 5.
Derivatives of formula (IV: R1 and/or R2 is H; I; Br; aryl; heteroaryl; X is O-alkyl) can be prepared according to Scheme 3. The p-hydroxybenzaldehyde (VIII) can be conveniently iodinated to the diiodophenol of formula (VIIIa: R1 and R2 is I) using at least two molar equivalents of iodine in the presence of two or more molar equivalents of an alkali metal hydroxide such as NaOH in an alcohol solvent such as methanol at xe2x88x9220xc2x0 C. to room temperature. Similarly the monoiodophenol (VIIIa: R1 is H; R2 is I) can be prepared from the phenol of formula (VIII) using one to 1.5 molar equivalents of iodine in the presence of at least one equivalent of an alkali metal hydroxide such as NaOH in a alcohol solvent such as methanol at xe2x88x9220xc2x0 C. to room temperature. Either the monoiodophenol (VIIIa: R1 is H; R2 is I) or the diiodophenol (VIIIa: R1 and R2 is I) can be converted to the respective alkyl ether derivatives of formula (VIIIb: R1 is H; R2 is I; X is xe2x80x94O-alkyl) or (VIIIb: R1 and R2 is I; X is xe2x80x94O-alkyl) by reacting the phenol moiety with a suitable alkylating agent such as one or more molar equivalents of methyl iodide or dimethylsulfate employing a base such an alkali methyl carbonate or hydroxide such as potassium carbonate or sodium hydroxide in a suitable solvent such as THF, DMFN or DMSO. The reaction is generally performed at temperatures ranging from 0xc2x0 C. to 60xc2x0 C. The mono or dibrominated benzaldehydes of formula (VIIIb: R1 and/or R2 is Br; X is xe2x80x94O-alkyl) can be prepared in analogs fashion by substituting bromine for iodine in the sequence above.
The mono or diiodo alkyl ether benzaldehydes of formula (VIIIb: R1 and/or R2 is I; X is O-alkyl) can be reacted with an arylboronic acid or heteroarylboronic acid to afford the product of formula (VIIIc: R1 and/or R2 is aryl or heteroaryl; X is xe2x80x94O-alkyl) under the conditions of the Suzuki Reaction (Journal of the Chemical Society Chemical Communications 1979 886 and Synthetic Communications 1981 11(7) 513). The other co-reagents necessary to effect the Suzuki Reaction include one or more molar equivalents of a metal catalyst such as tetrakis(triphenylphosphine)palladium or palladium (II) acetate and a base such as barium hydroxide octahydrate or sodium carbonate in a solvent such as benzene, toluene or DME/H2O. The starting aryl or heteroaryl boronic acids are commercially available or can be prepared by standard synthetic methods.
The mono or diaryl or mono or diheteroaryl benzaldehyde analogs of formula (VIIIc: R1 and/or R2 is aryl or heteroaryl; X is xe2x80x94O-alkyl) can be converted to the corresponding mono or diaryl or mono or diheteroaryl benzoic acid analogs of formula (VIIId: R1 and/or R2is aryl or heteroaryl; X is xe2x80x94O-alkyl) using the oxidative conditions of silver (I) oxide in an aqueous base such as sodium hydroxide at temperatures ranging from 50xc2x0 C. to reflux.
The benzoic acid compound (VIII: R1 and/or R2 is H; I; Br; aryl; heteroaryl; X is O-alkyl) can be converted to the corresponding benzoic acid chloride (IV: R1 and/or R2 is H; I; Br; aryl heteroaryl; X is O-alkyl) by standard procedures using reagents such as oxalyl chloride and thionyl chloride. The compounds prepared in Scheme 3 of formula (IV: R1 and/or R2 is H; I; Br; aryl; heteroaryl; X is O-alkyl) can be utilized in Scheme-xe2x88x921 to prepared compounds of formula (I: R1 and/or R2 is H; I; Br; aryl; heteroaryl). 
In an analogous synthetic sequence to Scheme 3, compounds of formula (Va: X is OH; R1 and/or R2 is H) can be functionalized at positions R1 and R2 to give compounds of formula (V: X is O-alkyl; R1 and/or R2 is H; I; Br; aryl; heteroaryl). The compounds prepared in Scheme 4 of formula (V: R1 and/or R2 is H; I; Br; aryl; heteroaryl; X is O-alkyl) can be utilized in Scheme 1 to prepared compounds of formula (I: R1 and/or R2 is H; I; Br; aryl; heteroaryl). The compounds prepared in Scheme 4 of formula (V: R1 and/or R2 is H; I; Br; aryl; heteroaryl; X is O-alkyl) can be synthetically modified in Scheme 5. 
In a three step process (Scheme 5) compounds of formula (Va: X is OH) can be converted to compounds of formula (Vb: X is xe2x80x94CH2NH2). Reaction of compounds of formula (Va: X is OH) with trifluoromethanesulfonic anhydride or trifluoromethanesulfonic acid chloride in the presence of a organic base such as pyridine or triethylamine in dichloromethane at 0xc2x0 C. to ambient temperature provides compound (IX). The triflate (IX) can be converted to the carbonitrile (X) with potassium cyanide or zinc cyanide in the presence of tetrakistriphenylphosphinenickel(0) which can be generated in situ from bistriphenylphosphinenickel (II) bromide and ZnPPh3. The nitrile (X) can be reduced to the aminoalkyl compound (Vb: X is xe2x80x94CH2NH2) by tin (II) chloride in refluxing ethyl acetate or by catalytic hydrogenation in the presence of a catalyst such as Raney nickel or by lithium aluminum hydride in an inert solvent such as ether.
From Scheme 5, the prepared compounds of formula (Vb: X is xe2x80x94CH2NH2) can be used in Scheme 1 to prepared sulfonamides of formula (I: X is xe2x80x94CH2NHxe2x80x94). 
In Scheme 6, the aldehyde (XI) can be prepared from commercially available furan (III: W is O ) using phosphorus oxychloride in dimethyl formaldehyde at 85xc2x0 C. under an inert atmosphere. Compound (XI) is treated with one to 1.3 molar equivalents of an suitable Wittig reagent in a nonprotic solvent such as THF at temperatures ranging from xe2x88x9278xc2x0 C. to room temperature under an inert atmosphere such as nitrogen or argon to provide the olefin derivative. The olefin (Vc: Y is xe2x80x94CHxe2x95x90CHxe2x80x94) can be converted to the alkane (Vd: Y is xe2x80x94CH2CH2xe2x80x94) through any standard procedure for hydrogenation. The most convenient method of reduction is catalytic hydrogenation employing 10% palladium on carbon over an atmosphere of hydrogen for 12-24 hours.
The compounds prepared in Scheme 6 of formula (Vc: Y is xe2x80x94CHxe2x95x90CHxe2x80x94) or (Vd: Y is xe2x80x94CH2CH2xe2x80x94) can be utilized in Scheme 1 to prepared compounds of formula (I: Y is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CH2CH2xe2x80x94). The compounds prepared in Scheme 6 can be synthetically modified in Schemes 4 and 5. 
Compounds of formula (Ve: Y is xe2x80x94NHCH2xe2x80x94) in Scheme 7 can be prepared through a number of reductive amination procedures such as the method of Maryanoff, et. al. (J. Org. Chem. 1996, 61, 3849-62), but is easily prepared by a modified procedure of Borch, et. al. (J. Am. Chem. Soc. 1971, 93, 2897-04. A solution of the aldehyde (XI) (as prepared in Scheme 6), and the appropriate aniline hydrochloride (XIII) (1.2-1.5 equivalent) in a suitable protic solvent such as methanol is stirred at room temperature in the presence of sodium cyanoborohydride (1.1-1.5 equivalent) yields compounds of formula (Ve: Y is xe2x80x94NHCH2xe2x80x94).
The compounds prepared in Scheme 7 of formula (Ve: Y is xe2x80x94NHCH2xe2x80x94) can be utilized in Scheme 1 to prepared compounds of formula (I: Y is xe2x80x94NHCH2xe2x80x94). The compounds prepared in Scheme 6 can be synthetically modified in Schemes 4 and 5.
The compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. The compounds of this invention are therefore, particularly useful in the treatment or inhibition of type II diabetes. The compounds of this invention are also useful in modulating glucose levels in disorders such as type I diabetes.
The ability of compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was established with representative compounds of this invention in the following standard pharmacological test procedure which measures the inhibition of PTPase.
Inhibition of Tri-Phosphorylated Insulin Receptor Dodecaphosphopeptide Dephosphorylation by hPTP 1B
This standard pharmacological test procedure assess the inhibition of recombinant rat protein tyrosine phosphatase, PTP1B, activity using, as substrate, the phosphotyrosyl dodecapeptide corresponding to the 1142-1153 insulin receptor kinase domain, phosphorylated on the 1146, 1150 and 1151 tyrosine residues. The procedure used and results obtained are briefly described below.
Human recombinant PTP1B was prepared as described by Goldstein (see Goldstein et al. Mol. Cell Biochem. 109, 107, 1992). The enzyme preparation used was in microtubes containing 500-700 xcexcg/ml protein in 33 mM Tris-HCl, 2 mM EDTA, 10% glycerol and 10 mM 2-mercaptoethanol.
Measurement of PTPase activity.
The malachite green-ammonium molybdate method, as described (Lanzetta et al. Anal. Biochem. 100, 95, 1979) and adapted for a platereader, is used for the nanomolar detection of liberated phosphate by recombinant PTP1B. The test procedure uses, as substrate, a dodecaphosphopeptide custom synthesized by AnaSpec, Inc. (San Jose, Calif.), the peptide, TRDIYETDYYRK, corresponding to the 1142-1153 catalytic domain of the insulin receptor, is tyrosine phosphorylated on the 1146, 1150, and 1151 tyrosine residues. The recombinant rPTP1B is diluted with buffer (pH 7.4, containing 33 rnM Tris-HCl, 2 mM EDTA and 50 mM b-mercaptoethanol) to obtain an approximate activity of 1000-2000 nmoles/min/mg protein. The diluted enzyme (83.25 mL) is preincubated for 10 min at 37xc2x0 C. with or without test compound (6.25 mL) and 305.51 mL of the 81.83 mM HEPES reaction buffer, pH 7.4 peptide substrate, 10.5 ml at a final concentration of 50 mM, and is equilibrated to 37xc2x0 C. in a LABLINE Multi-Blok heater equipped with a titerplate adapter. The preincubated recombinant enzyme preparation (39.5 ml) with or without drug is added to initiate the dephosphorylation reaction, which proceeds at 37xc2x0 C. for 30 min. The reaction is terminated by the addition of 200 mL of the malachite green-ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw). The stopping reagent consists of 3 parts 0.45% malachite green hydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCl and 0.5% Tween 20. Sample blanks are prepared by the addition of 200 mL MG/AMJFw to substrate and followed by 39.5 ml of the preincubated recombinant enzyme with or without drug. The color is allowed to develop at room temperature for 30 min. and the sample absorbances are determined at 650 nm using a platereader (Molecular Devices). Sample and blanks are prepared in quadruplicates.
Calculations:
PTPase activities, based on a potassium phosphate standard curve, are expresses as nmoles of phosphate released/min/mg protein, inhibition of recombinant PTP1B by test compounds is calculated as percent of phosphatase control. A four parameter non-linear logistic regression of PTPase activities using SAS release 6.08, PROC NLIN, is used for determining IC50 values of test compounds. The following results were obtained.
Based on the results obtained in the standard pharmacological test procedure, representative compounds of this invention have been shown to inhibit PTPase activity and are therefore useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. More is invention useful in the treatment or inhibition of type II diabetes, and in modulating glucose levels in disorders such as type I diabetes. As used herein, the term modulating means maintaining glucose levels within clinically normal ranges.
Effective administration of these compounds may be given at a daily dosage of from about 1 mg/kg to about 250 mg/kg, and may given in a single dose or in two or more divided doses. Such doses may be administered in any manner useful in directing the active compounds herein to the recipient""s bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally. For the purposes of this disclosure, transdermal admininistrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s). Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository""s melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.
It is understood that the dosage, regimen and mode of administration of these compounds will vary according to the malady and the individual being treated and will be subject to the judgment of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
The following procedures describe the preparation of representative examples of this invention.